This invention relates to rapamycin polymorph Form II.
Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which was initially identified as having antifungal activity, particularly against Candida albicans, both in vitro and in vivo (C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J Antibiot. 28, 727 (1975); H. A. Baker et al, J Antibiot. 31, 539 (1978); U.S. Pat. Nos. 3,929,992 and 3,993,749). Rapamycin is commercially available as Sirolimus (Wyeth).
Rapamycin is widely used as an immunosuppressant in organ transplant recipients and has shown limited toxicities even in combination schedules with other immunosuppressants like cyclosporine or corticosteroids. The intracellular rapamycin receptor is a small protein termed FKBP12 (FK506-binding protein). The FKBP-rapamycin complex inhibits the function of a serine/threonine kinase, mTOR (mammalian target of rapamycin), thereby blocking stimulation of the ribosomal s6 kinase p70s6 kinase (p70s6k). p70s6k in turn phosphorylates the 40s ribosomal protein S6, which favors translation of mRNAs that encode ribosomal proteins and elongation factors. Another target of mTOR is a low-molecular-weight repressor of translation initiation termed phosphorylated heat- and acid-stable protein regulated by insulin (PHAS-I). Phosphorylation of PHAS-I results in its dissociation from eukaryotic initiation factor (eIF)-4E and increases eIF-4E-dependent translation initiation.
Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human T cells and B cells. In addition, rapamycin has in vitro and in vivo activity against a broad range of human tumor cell lines and is considered to represent a promising new class of cytostatic anticancer agents.